Synthesis, in silico and kinetics evaluation of N-(β-D-glucopyranosyl)-2-arylimidazole-4(5)-carboxamides and N-(β-D-glucopyranosyl)-4(5)-arylimidazole-2-carboxamides as glycogen phosphorylase inhibitors

Abstract

Recently studied N-(β-D-glucopyranosyl)-3-aryl-1,2,4-triazole-5-carboxamides proved to be low micromolar inhibitors of glycogen phosphorylase (GP), a validated target for the treatment of type 2 diabetes mellitus. Since in other settings, the bioisosteric replacement of the 1,2,4-triazole moiety by imidazole resulted in significantly more efficient GP inhibitors, in silico calculations using Glide molecular docking along with unbound-state DFT calculations was performed on N-(β-D-glucopyranosyl)-arylimidazole-carboxamides revealing potential for strong GP inhibition. The syntheses of the target compounds involved formation of an amide bond between per-O-acetylated β-D-glucopyranosylamine and the corresponding arylimidazole-carboxylic acids. Kinetics experiments against rabbit muscle GPb revealed low micromolar inhibitors with the best inhibition constants (Kis) of ~ 3-4 µM obtained for 1- and 2-naphthyl substituted N-(β-D-glucopyranosyl)-imidazolecarboxamides, 2b-c. The predicted protein-ligand interactions responsible for the observed potencies are discussed and will facilitate the structure-based design of other inhibitors targeting this important therapeutic target. Meanwhile, the importance of careful consideration of ligand tautomeric states in binding calculations is highlighted, with the usefulness of DFT calculations in this regard proposed.